Part Two Investigating New Treatment Opportunities For Patients With Chronic Kidney Disease in Type 2 Diabetes: The Role Of Finerenone
May 30, 2023
Finerenone Phase iii project
FIDELIO-DKD and FIGARO-DKD are large-scale (n ¼ 5674 and n ¼ 7354, respectively) international, randomized, double-blind, placebo-controlled trials investigating the efficacy and safety of finer enone in reducing CKD progression and CV mortality and morbidity in patients with CKD and T2D [43, 44]. The studies enrolled patients from 48 countries and territories across 6 continents (Figure 3 and Supplementary data, Figure 1) [43, 44].
FIDELIO-DKD and FIGARO-DKD are independent event-driven trials that individually, with the total number of primary endpoints accrued, provide a minimum of 90% power to detect a 20% relative risk reduction in their respective primary endpoints with finer enone compared with placebo. The trials were designed to include common and reciprocal primary and key secondary endpoints consisting of important and relevant renal and CV outcomes (Figure 3). The FIDELIO-DKD primary endpoint is a composite of time to first occurrence of kidney failure, defined as either the initiation of chronic dialysis over 90 days or renal transplantation (ESKD) or a sustained eGFR <15 mL/min/1.73 m2 over at least 4 weeks, a sustained decrease in eGFR of 40% from baseline over at least 4 weeks or renal death, whereas the key prespecified secondary endpoint is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for heart failure [43]. The FIGARO-DKD primary endpoint is the composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure, with the key prespecified secondary endpoint replicating the primary composite endpoint of FIDELIO-DKD (Figure 3) [43, 44]
Other secondary endpoints include deaths and hospitalizations from any cause. Exploratory endpoints such as annualized eGFR slope will also be studied. In addition, the trials will prospectively assess the change in health-related quality of life, which will be evaluated in all patients using the 36-item Kidney Disease Quality of Life and 5-level European Quality of Life 5- Dimensions questionnaires. Moreover, the trials will include echocardiography and biomarker substudies, thereby contributing a depth of insight that considers pathophysiology as well as patient-centered outcomes, aspects that have not been previously addressed to this extent in this patient population.
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Comparing FIGARO-DKD and FIDELIO-DKD populations with other trials in CKD with T2D
Patients with preserved eGFR are often excluded from CKD with T2D trials. Previously understudied patient groups concerning renal and CV outcomes, such as those with high albuminuria (UACR 30–<300 mg/g) or very high albuminuria (UACR >300 mg/g) and eGFR >60 mL/min/1.73 m2 (Figure 4A and Table 1) is now well represented. In total, 39.9% (5196/ 13 028) of patients included in both trials corresponded to this population with preserved eGFR.
To better quantify cardiorenal risk in the FIDELIO-DKD and FIGARO-DKD patient populations we used a validated tool. The KDIGO CKD working group uses a combination of eGFR and UACR categories in its risk stratification tool for predicting CKD and CV outcomes [12]. The results are shown in Figure 4B. Across the two trials, moderate, high, and very high KDIGO risk scores were noted in 10, 41.1, and 48.3% of patients, respectively; ~90% had at least a high risk of a major clinical outcome.
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To further compare the FIDELIO-DKD and FIGARO-DKD patient populations with other trials we plotted the summary estimates of baseline UACR and eGFR data enrolled in recent CKD in T2D trials investigating CV and/or renal outcomes (Figure 5; Supplementary data, Figure 2 and Supplementary data, Table 2). The high albuminuria population is underrepresented in other trials but is well represented in the FIDELIODKD and FIGARO-DKD program, where 4070 (31.2%) patients have high albuminuria at baseline (Figure 5; Supplementary data, Figure 2 and Supplementary data, Table 2). Albuminuria is an independent risk marker for CV and all-cause mortality, even at levels within the upper normal range [8, 9]. Accordingly, this high-risk CV population should allow for greater insight into the possible benefit of finer enone for reducing CV outcomes in this group of patients with earlier stages of CKD.
Despite the pooled trial population being at high risk of CV events and having a lower mean eGFR at baseline compared with the CREDENCE (Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation) trial of canagliflozin in patients with T2D and CKD (Table 1; Supplementary data, Table 2 and Supplementary data, Figure 2), the FIDELIODKD and FIGARO-DKD population was well-controlled relative to the CREDENCE trial concerning lower baseline HbA1c and systolic blood pressure (Table 1; Supplementary data, Table 2). Evaluating a well-controlled patient population minimizes variation and confounding factors within the trial outcomes. Furthermore, it allows validation of the potential cardiorenal benefit of finer enone in addition to the best standard of care for glycemic control and CV risk.
The FIDELIO-DKD and FIGARO-DKD trials are designed to investigate the effect of finer enone on reducing the risk of CV disease in FIGARO-DKD as well as CKD progression in FIDELIO-DKD, but cross-validating the findings within one trial program. No previous trial program has been designed this way. As with other trials, FIDELIO-DKD and FIGARO-DKD investigated patients receiving the approved standard of care with the maximum tolerated labeled doses of ACEi or ARB (Table 1). In addition, ~7% of patients included also received SGLT2is and glucagon-like peptide-1 receptor agonists at baseline (Table 1). Although the population receiving SGLT2is in the FIDELIO-DKD and FIGARO-DKD trials is comparatively small, this subgroup may provide insights into the effects of receiving both finer enone and SGLT2i.
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Conclusions
The FIDELIO-DKD and FIGARO-DKD studies comprise the largest CKD outcomes program to date and will determine the effect of a novel approach to the treatment of CKD in T2D that targets the underlying disease processes. This approach extends the CKD patient reach by including previously understudied and high-risk cardiorenal subgroups. As such, the trials deliberately included patients with high and very high albuminuria at high cardiorenal risk despite the best standard of care for glycemic control and control of CV risk factors (Table 1). Also, the trials are powered to demonstrate both efficacy and safety on the major kidney and CV outcomes in this high-risk population. Finally, the FIDELIO-DKD and FIGARO-DKD trials are prespecified superiority studies as opposed to safety trials and evaluate a treatment that does not have a glucose-lowering effect. These trials have the potential to reduce CKD progression and afford cardiorenal protection in patients with T2D across the CKD continuum. The trials are anticipated to complete in 2020 and 2021, respectively
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Rajiv Agarwal 1 , Stefan D. Anker2 , George Bakris3 , Gerasimos Filippatos4 , Bertram Pitt5 , Peter Rossing6,7, Luis Ruilope8,9,10, Martin Gebel11, Peter Kolkhof12, Christina Nowack13 and Amer Joseph14; on behalf of the FIDELIO-DKD and FIGARO-DKD Investigators
1 Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN, USA,
2 Department of Cardiology (CVK) and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charite´ Universita¨tsmedizin, Berlin, Germany,
3 Department of Medicine, University of Chicago Medicine, Chicago, IL, USA,
4 National and Kapodistrian University of Athens, School of Medicine, Department of Cardiology, Attikon University Hospital, Athens, Greece,
5 Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA,
6 Steno Diabetes Center Copenhagen, Gentofte, Denmark,
7 Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark,
8 Cardiorenal Translational Laboratory and Hypertension Unit, Institute of Research imas12, Madrid, Spain,
9 IBER-CV, Hospital Universitario, 12 de Octubre, Madrid, Spain,
10 Faculty of Sport Sciences, European University of Madrid, Madrid, Spain,
11 Research and Development, Statistics and Data Insights, Bayer AG, Berlin, Germany,
12 Research and Development, Preclinical Research Cardiovascular, Bayer AG, Wuppertal, Germany,
13 Research and Development, Clinical Development Operations, Bayer AG, Wuppertal, Germany
14 Cardiology and Nephrology Clinical Development, Bayer AG, Berlin, Germany
